Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India.
Curr Drug Targets. 2021;22(11):1288-1316. doi: 10.2174/1389450122666210203194036.
Hepatocellular carcinoma (HCC) is one of the most common solid tumours and the second leading cause of cancer-related mortality worldwide. Advanced-recurrent HCC often requires a systemic drug therapy where multi tyrosine kinase inhibitor, Sorafenib represents the first-line therapy option. But it exhibited very limited survival benefit and tumour response due to the early emergence of drug resistance and drug-related adverse effect. Immunotherapy approaches now being widely studied as an effective alternative treatment for HCC. Several immune checkpoint inhibitors (ICI), such as Nivolumab and Pembrolizumab, are approved as monotherapy in sorafenib-resistant HCC patients. But, the existence of a plethora of immunosuppressive signals in the tumour microenvironment often leads to unsuccessful immunotherapies. In this context, combinatorial immunotherapies are getting much acceptance as a way to improve therapeutic outcomes by blocking immunosuppressive signals in the tumour microenvironment (TME). The combination of Vascular Endothelial Growth Factor (VEGF) inhibitors with ICI resulted in significant synergistic effects in various preclinical and clinical studies. However, the adverse effects associated with current synthetic VEGF inhibitors limit its clinical utility. In this review, we have summarized the potential of phytochemicals, especially the category of flavonoids, alkaloids, glycosides, terpenoids, and coumarin, as the available-affordable-safe-effective repositories of VEGF inhibitors. Their possibilities as an alternative for synthetic VEGF inhibitors by synergistic combination with ICI are reviewed, thereby enhancing patient compliance and survival rates. This review highlights the demand for a detailed investigation of the plausible role of plant-based anti-angiogenic-immunotherapy combination against HCC.
肝细胞癌 (HCC) 是最常见的实体肿瘤之一，也是全球癌症相关死亡的第二大主要原因。晚期复发性 HCC 通常需要系统药物治疗，其中多酪氨酸激酶抑制剂索拉非尼是一线治疗选择。但由于药物耐药性和药物相关不良反应的早期出现，其表现出非常有限的生存获益和肿瘤反应。免疫疗法目前正在广泛研究作为 HCC 的有效替代治疗方法。几种免疫检查点抑制剂 (ICI)，如纳武单抗和帕博利珠单抗，已被批准作为索拉非尼耐药 HCC 患者的单药治疗。但是，肿瘤微环境中存在大量的免疫抑制信号，通常导致免疫疗法失败。在这种情况下，联合免疫疗法作为一种通过阻断肿瘤微环境 (TME) 中的免疫抑制信号来提高治疗效果的方法越来越受到认可。血管内皮生长因子 (VEGF) 抑制剂与 ICI 的联合在各种临床前和临床研究中产生了显著的协同作用。然而，目前合成 VEGF 抑制剂相关的不良反应限制了其临床应用。在这篇综述中，我们总结了植物化学物质（尤其是黄酮类、生物碱类、糖苷类、萜类和香豆素类）作为 VEGF 抑制剂的潜在来源，具有可获得、负担得起、安全和有效的特点。综述了它们与 ICI 联合作为合成 VEGF 抑制剂的替代品的可能性，从而提高了患者的依从性和生存率。这篇综述强调了对基于植物的抗血管生成免疫联合治疗 HCC 的潜在作用进行详细研究的需求。
